Polyneuropathy is a common and often debilitating complication of diabetes. In several animal models of diabetic neuropathy, it has been demonstrated that trophic factors administered by systemic injection may prevent progression or reverse signs of neuropathy. But translation of systemic trophic factor therapy to human disease has not succeeded, in large part because patients have proven to be unable or unwilling to tolerate the range of doses that are required to achieve a therapeutic effect. We have engineered and developed recombinant replication-incompetent genomic herpes simplex virus (HSV)-based vectors for gene transfer to the nervous system, and in the initial grant proposed to exploit the natural tropism of these vectors for peripheral sensory neurons of the dorsal root ganglion (DRG) to test the hypothesis that neurotrophin gene transfer to the DRG by means of an HSV-based vector can be prevent the progression of diabetic neuropathy. We now propose to extend these studies to accomplish two groups of specific aims, designed to explore the most effective strategy for the development of a novel therapy for diabetic neuropathy and to explore the molecular basis of that effect. Specific Aim 1. To define the time course of protection against diabetic neuropathy comparing transiently active promoter with a promoter that provides prolonged transgene expression. Specific Aim 2. To determine the dose-response characteristics of the vector-mediated effect. Specific Aim 3. To determine whether HSV-mediates gene transfer of IGF-1 or VEGF165 alone or in combination with NGF, is effective in preventing the progression of diabetic neuropathy. Specific Aim 4. To examine the effect of STZ diabetes on the alteration in gene expression in DR (neurons and Schwann cells in vivo, and to identify specific alterations in that expression that are reversed by vector transduction. Specific Aim 5. To construct a vector with a regulatable "switch" to control transgene expression safe). Diabetic neuropathy is a difficult complication of the primary disease. Factors of known therapeutic efficacy have been identified in animals models, and we have made substantial progress in constructing a vector to deliver these factors to the peripheral nervous system. The studies in this proposal are designed to allow the development of an effective therapy appropriate for the treatment of patients.